The invention relates generally to the controlled release of macromolecules, and particularly, to the preparation of a copolymer useful in release of such macromolecules.
The sustained release of active agents is known to be of value. In particular, long-term drug delivery has been shown to be effective in obtaining constant serum levels and in improving patient compliance.
It is well known in the art that hydrogel membranes may be used for sustained delivery of active compounds. There are several theories regarding the mechanism of solute diffusion in hydrogels. Lee et al., J. Polymer Science: Polymer Symposium, 66:227-237 (1979) hypothesized that there are three classes of water in hydrogels, including, xe2x80x9cZxe2x80x9d water which is bound to the polymer matrix, xe2x80x9cYxe2x80x9d water which is partially affected by the polymer matrix, and bulk or xe2x80x9cXxe2x80x9d water which is unaffected by the polymer matrix. Kim et al., ACS Symp. Ser., 127:347-359 (1980) expanded upon the Lee model. Kim et al, concluded that the diffusion of hydrophilic solutes through hydrogel membranes depends on molecular size of the solute and water content of the hydrogel and that the permeation takes place via the bulk water.
The hydrogels which have been described in the art have some porosity, due to the network structure of the crosslinked polymer chains, which allow smaller molecules to diffuse through the structure. The size of the pores varies depending upon the hydrogel chemical composition and thus, its degree of hydration (equilibrium water content, xe2x80x9cEWCxe2x80x9d). However, the hydrogels described in the art are not particularly well adapted to delivery of large molecules (macromolecules).
What is needed in the art are compositions which are well suited for sustained delivery of macromolecules and methods for producing these compositions.
In a first aspect, the present invention provides a method for preparing a homogenous porous hydrogel which permits sustained delivery of macromolecules. The method involves mixing about 60 weight percent to about 95 weight percent comonomers, at least one of which is hydrophilic, and sufficient amounts of a crosslinker and a liquid diffusion enhancer which is miscible with the comonomers, to yield a homogenous copolymer hydrogel having the equilibrium water content (EWC) value in the range from about 20% to about 85%. The methods and compositions of the invention are particularly well suited to rotational casting of the hydrogel into the form of a cartridge, which preferably has walls of uniform thickness which define a reservoir. The hydrogel of the invention is useful for sustained release of macromolecular compounds having a molecular weight of up to 100,000.
In a preferred embodiment, the polymerizable liquid mixture contains about 1 weight percent to about 50 weight percent diffusion enhancer which may be readily selected from among C1-C4 alkyl alcohol, allyl alcohol, tetrahydrofurfuryl alcohol, cyclohexyl alcohol, diethylene glycol, polyethylene glycols, glycerol, acetone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glyceryl isopropylidene ether dioxane, tetrahydrofuran; ethyl acetate; dimethyl sulfoxide; water, and mixtures thereof.
In another aspect, the invention provides an article produced according to the method of the invention.
In yet another aspect, the invention provides a method for the preparation of a delivery device for the sustained release of an active agent. This method involves introducing an active agent, and optionally, a pharmaceutically acceptable carrier, into the reservoir of a cartridge prepared according to the invention. Subsequently, at least one polymerizable liquid monomer is added into the upper portion of the reservoir and is then polymerized to seal the opening of the reservoir with a plug of water-swellable, water-insoluble polymer to form a delivery device which provides a predetermined release of the active agent.
In still another aspect, the invention provides a delivery device prepared according to the method above.
Other aspects and advantages of the invention will be readily apparent from the detailed description of the invention.